The present invention generally relates to the characterization of liquid samples by optical techniques, and in preferred embodiments, characterization of polymer samples and non-polymer samples by light-scattering techniques. In particular, the invention relates to methods and apparatus for characterizing liquid samples (e.g. solutions, emulsions, suspensions and/or dispersions) by serial or parallel analysis to determine commercially important properties of the samples or components thereof, such as particle size or particle size distribution. In preferred embodiments, the characterization of the liquid samples or of components thereof is effected in parallel with a probe head comprising an array fiber optic probes suitable for static light scattering and/or dynamic light scattering. The methods and devices disclosed herein are applicable, inter alia, to high-throughput characterization of liquid samples, and especially samples prepared by combinatorial materials science techniques.
Currently, there is substantial research activity directed toward the discovery and optimization of polymeric materials and other materials for a wide range of applications. Although the chemistry of many materials (e.g. polymers) and synthesis reactions (e.g. polymerization) has been extensively studied, it is, nonetheless, rarely possible to predict a priori the physical or chemical properties a particular material will possess or the precise composition and architecture that will result from any particular synthesis scheme. Thus, characterization techniques to determine such properties are an essential part of the discovery process.
Combinatorial chemistry, also referred to as combinatorial materials science and/or high-throughput experimentation, refers generally to methods for synthesizing a collection of chemically diverse materials and to methods for rapidly testing or screening this collection of materials for desirable performance characteristics and properties. Combinatorial chemistry approaches have greatly improved the efficiency of discovery of useful materials. For example, material scientists have developed and applied combinatorial chemistry approaches to discover a variety of novel materials, including for example, high temperature superconductors, magnetoresistors, phosphors and catalysts. See, for example, U.S. Pat. No. 5,776,359 to Schultz et al., U.S. Pat. No. 5,985,356 to Schultz et al., U.S. Pat. No. 6,004,617 to Schultz et al., and U.S. Pat. No. 6,030,917 to Weinberg et al. In comparison to traditional materials science research, combinatorial materials research can effectively evaluate much larger numbers of diverse compounds in a much shorter period of time. Although such high-throughput synthesis and screening methodologies are conceptually promising, substantial technical challenges exist for application thereof to specific research and commercial goals.
Methods have been developed for the combinatorial (e.g., rapid-serial or parallel) synthesis and screening of libraries of small molecules of pharmaceutical interest, and of biological polymers such as polypeptides, proteins, oligonucleotides and deoxyribonucleic acid (DNA) polymers. However, there have been few reports of the application of combinatorial techniques to the field of polymer science for the discovery of new polymeric materials or polymerization catalysts or new synthesis or processing conditions. Brocchini et al. describe the preparation of a polymer library for selecting biomedical implant materials. See S. Brocchini et al., A Combinatorial Approach for Polymer Design, J. Am. Chem. Soc. 119, 4553-4554 (1997). However, Brocchini et al. reported that each synthesized candidate material was individually precipitated, purified, and then characterized according to xe2x80x9croutine analysisxe2x80x9d that included gel permeation chromatography to measure molecular weight and polydispersities. As such, Brocchini et al. did not address the need for efficient and rapid characterization of polymers.
High-throughput screening approaches have also been developed for a number of combinatorial material science applications, including applications directed toward polymer characterization and toward the identification of useful catalysts. Exemplary approaches are disclosed, for example, in the aforementioned related patent applications, as well as in the following published applications and/or patents: PCT application WO 97/32208 of Willson; U.S. Pat. No. 5,959,297 to Weinberg et al.; PCT application WO 99/64160 of Guan et al.; PCT application WO 00/09255 of Turner et al.; and PCT application WO 00/51720 of Bergh et al.
Light scattering techniques, both static and dynamic, are known in the art for characterizing particle size and shape, and particle size distribution of micron and submicron size materials, among them colloidal dispersions, emulsions, suspensions and/or solutions of inorganic molecules, biological macromolecules or polymers, and/or non-biological polymers.
Dynamic light scattering (DLS) or quasielastic light scattering (QELS) measures the fluctuation of scattered light intensity of suspended fluids or particles exhibiting Brownian motion. For example, and without being bound by theory not specifically recited in the claims, measurement of such intensity fluctuations and autocorrelation techniques can yield the normalized intensity-intensity autocorrelation function g2(t) that allows measurement of the particle diffusion coefficient D:
xe2x80x83g2(t)=xcex2exp(xe2x88x922q2Dt)xe2x80x83xe2x80x83(1),
where, xcex2 is an instrument parameter (0 less than xcex2 less than 1), and the scattering vector q is related to the scattering angle xcex8, the incident laser wavelength xcex, and the refractive index n of the fluid medium by                     q        =                                            4              ⁢                              xe2x80x83                            ⁢              π              ⁢                              xe2x80x83                            ⁢              n                        λ                    ⁢                                    sin              ⁡                              (                                  θ                  2                                )                                      .                                              (        2        )            
The diffusion coefficient D is related to the hydrodynamic radius Rh of the particle as:                     D        =                  kT                      6            ⁢            πη            ⁢                          xe2x80x83                        ⁢                          R              h                                                          (        3        )            
where T is the temperature in Kelvin, k is the Boltzman constant, xcex7 is the viscosity of the fluid medium. Although often the primary quantity of interest is the particle size, other quantities of interest like diffusion coefficient may be probed with tracer particles of a defined hydrodynamic radius. Further details of the technique of dynamic light scattering and autocorrelation is described for example in various patents such as U.S. Pat. No. 4,975,237 to Brown, U.S. Pat. No. 4,983,040 to Chu et al., and U.S. Pat. No. 5,011,279 to Autweter et al., and in monographs such as Chu, xe2x80x9cLaser light scattering: basic principles and practicexe2x80x9d, Academic Press 1991; Berne, xe2x80x9cDynamic light scattering: with applications to chemistry, biology, and physicsxe2x80x9d, Wiley 1976. Dynamic light scattering methods may also be used to determine the average molar mass and molar mass distribution of a polymer. See, for example, Burchard, xe2x80x9cLight Scattering Principles and Developmentxe2x80x9d, Ed. by W. Brown, Clarendon Press 1996.
Static light scattering (SLS) techniques are also well known, and can be used for example, to measure Mw and the radii of gyration (Rg) of a polymer in a dilute solution of known concentration. Apparatus and methods suitable for static light scattering are described in the references mentioned in the immediately preceding paragraph.
With the development of combinatorial techniques that allow for the parallel synthesis of arrays comprising a vast number of diverse industrially relevant polymeric and non-polymeric materials, there is a need for methods, devices and systems to rapidly characterize the properties of the synthesized polymer and non-polymer samples.
It is therefore an object of the present invention to provide systems and protocols for characterizing combinatorial libraries of polymer samples and non-polymer samples, and particularly, libraries of or derived from synthesis reactions such as polymerization product mixtures, or libraries of or derived from formulations (e.g., of nanodispersion formulations). Such characterization can facilitate the discovery of commercially important polymeric and non-polymeric materials, formulations, catalysts, synthesis (e.g. polymerization) conditions and/or post-synthesis processing conditions. It is also an object of the invention to provide characterization systems and protocols that can be employed in near-real-time industrial process control.
Briefly, therefore, this invention provides a number of approaches for rapid characterization or screening of liquid samples comprising polymers and non-polymer components. The various embodiments disclosed and claimed herein can be employed individually or combined together, and can be combined with other approaches such as those disclosed in the aforementioned related applications. More specifically, characterization approaches and devices are presented involving non-flow characterization with rapid-serial, parallel, serial-parallel and hybrid parallel-serial approaches. Some preferred approaches and embodiments are directed to parallel non-flow characterization of liquid samples.
The invention is directed, in one embodiment, to a method for characterizing a liquid sample or a component thereof. According to the method, a liquid sample having an exposed surface that defines a gas-liquid sample interface is provided. The sample is analyzed by light-scattering methods that include transmitting light into the sample and detecting light scattered from the sample or a component thereof. The light is transmitted or detected through the gas-liquid sample interface. In preferred embodiments, the light is transmitted into the sample through the gas-liquid sample interface, with the scattered light being detected through the same gas-liquid sample interface, or alternatively, through a bottom or side of a sample-holding container. In particularly preferred embodiments, the light is both transmitted and detected through the gas-liquid sample interface. As such, illumination and detection are preferably effected without immersion of a detection probe into the sample. A property of interest can be determined from the detected light (e.g. from the amount or intensity of the detected light or from the intensity fluctuations associated with the detected light).
The invention is also directed to methods for characterizing a plurality of liquid samples or components thereof in rapid-serial, serial-parallel or parallel operational modes.
According to one embodiment, a plurality of liquid samples are provided, where each of the plurality of samples has an exposed surface that defines a gas-liquid sample interface. The plurality of samples are analyzed in parallel by light scattering methods that include simultaneously transmitting light into each of the plurality of samples, and detecting, preferably simultaneously detecting, light scattered from each of the plurality of samples or a component thereof. The light is transmitted or detected through the gas-sample interface of each of the plurality of samples. In preferred embodiments, the light is transmitted through the gas-liquid sample interface, with the scattered light from each of the samples being detected through the gas-liquid sample interface, or alternatively, through a bottom or side of a container holding each of the samples. In a particularly preferred embodiment, the light is both transmitted and detected through the gas-liquid sample interface. A property of interest can be determined from the detected light.
In each of the aforedescribed embodiments, the gas-liquid interface is preferably substantially planar in the region through which the incident light is transmitted, and if applicable, through which the scattered light is detected. In some embodiments, the shape of the gas-liquid interface is controlled such that a difference in scattering angle of not more than about 10xc2x0 results relative to the scattering angle from a perfectly planar gas-liquid interface.
According to another embodiment for characterizing a plurality of liquid samples or components thereof, a plurality of liquid samples, preferably four or more liquid samples, are providedxe2x80x94on a common sample holder or on two or more sample holders. A light scattering probe or an array comprising two or more light scattering probes (e.g., arranged in a probe head) are provided, and the system is adapted for relative translation of the sample holder(s) and/or probe(s)xe2x80x94such that the sample holder(s), the probe(s) or both can be moved relative to each other to effect a rapid-serial, serial-parallel or parallel operational mode.
More specifically, in a rapid-serial variation of such embodiment, a first sample of a plurality of liquid samples is analyzed by light scattering methods that include transmitting light from a probe into the first sample, and detecting light scattered from the first sample or a component thereof. The one or more sample holder and/or the probe are then translated relative to each otherxe2x80x94e.g., with the sample holder(s) moving relative to the probe, with the probe moving relative to the sample holder, or with both the sample holder(s) and the probe moving relative to each other. A second sample of the plurality of liquid samples is then analyzed by light scattering methods that include transmitting light from the probe into the second sample, and detecting light scattered from the second sample or a component thereof.
In a serial-parallel variation of such embodiment, four or more samples are characterized as follows. A first plurality of the four or more samples is analyzed in parallel by light scattering methods (e.g., by simultaneously transmitting light from each of the two or more probes into the first plurality of samples, respectively, and detecting, preferably simultaneously detecting, light scattered from each of the first plurality of samples or a component thereof). The first plurality of samples may be provided on a common (e.g., first) sample holder, or may be provided on separate sample holders. The sample holder(s) and/or the array of two or more probes are then translated relative to each otherxe2x80x94e.g., with the sample holder(s) moving relative to a stationary array of probes, with the array of probes moving relative to stationary sample holder(s), or with both the sample holder(s) and the array of probes moving relative to each other. A second plurality of the four or more samples is then analyzed in parallel (e.g. by light scattering methods that include simultaneously transmitting light from each of the two or more probes into the second plurality of samples, respectively, and detecting, preferably simultaneously detecting, light scattered from each of the second plurality of samples or a component thereof). The second plurality of samples may likewise be provided on a common (e.g. second) sample holder, or may be provided on separate sample holders.
In a parallel variation of such embodiment, a first plurality of liquid samples, and preferably a first set of four or more liquid samples are provided on a first common sample holder, and a second plurality of liquid samples, preferably a second set of four or more liquid samples are provided on a second common sample holder. The first and second sample holders can, optionally, be mounted, situated or positioned on a sample holder support. An array comprising two or more light scattering probes (e.g., arranged in a probe head) are provided, and the system is adapted for relative translation of the sample holders and/or probes. Preferably, the number of probes and the spatial arrangement of probes included within the array of probes corresponds, respectively, to the number of samples and the spatial arrangement of samples on each of the first and second sample sample holder. As such, relative motion between the sample holders and the array of the probes can effect characterization in a fully parallel operational mode with respect to the samples, on each sample holder.
The invention is further directed to a method for identifying useful materials.
In general, such methods can include characterizing a liquid sample, a plurality of samples or four or more samples by any of the aforementioned methods of the invention by analyzing the samples as described, determining a property of the samples from the detected scattered light (if not already required by such methods), and comparing the detected scattered light and/or the determined property.
In a preferred method for identifying useful materials, a library of liquid samples is provided, with the library comprising four or more different liquid samples (e.g. different polymer molecules/components, different inorganic compositions, different formulations, etc.). Such library is preferably a reaction product library such as a polymerization product library, a catalyst-synthesis reaction library, or a formulations product library (e.g., nanodispersion formulations). The four or more samples can be on a common sample holder, or on two or more separate sample holders. The four or more samples are analyzed in parallel by light scattering methods that include simultaneously transmitting light into at least four of the four or more samples, and detecting, preferably simultaneously detecting, light scattered therefrom or from a component thereof. A property of the at least four samples or of a component thereof can be determined, preferably simultaneously. The determined property of the at least four samples can be compared, with such comparison providing a basis (e.g., metric) for identifying a useful material.
In a particularly preferred variation of such embodiment, two or more sample holders (e.g., microtiter plates), each comprising a plurality (e.g., four or more) of different samples, can be arranged on a sample holder supportxe2x80x94for example, on a carousel surfacexe2x80x94adapted such that the array of probes can be used to analyze a plurality of samples in serial-parallel or parallel manner on a first sample holder, then subsequently, to analyze a pluarlity of samples in serial parallel or parallel on a second sample holder. Automated handling of sample holdersxe2x80x94such as six microtiter plates mounted on a sample holder support (mount) in a 2xc3x973 matrixxe2x80x94can facilitate very high throughput characterization.
The following more particular aspects of the invention are contemplated in connection with each of the aforedescribed embodiments. The sample is preferably a solution, emulsion, dispersion or suspension of polymers or non-polymers (e.g. inorganic elements or compounds), or a combination thereof (e.g., a sample comprising solvated components as well as dispersed components). The sample holder can be a common substrate comprising a number of vessels and/or wells integrally formed in the substrate and/or situated in the substrate. A microtiter plate is an exemplary sample holder. The light-scattering techniques are preferably static light scattering techniques and/or dynamic light scattering techniques. Other light-scattering techniques, such as fluorescence light scattering techniques can be used in connection with each of the embodiments of the invention. Additionally, other optical techniques, including optical spectroscopy techniques, such as infrared (IR) spectroscopy, ultraviolet (UV) spectroscopy, Raman spectroscopy and fluorescence spectroscopy are contemplated for use in connection with each of the embodiments of the invention, in addition to or alternatively to the light-scattering techniques disclosed herein. Hence, although the invention is described primarily with regard to such light-scattering techniques, the scope of the invention should not be unnecessarily limited by such exemplary description. The determined property is preferably particle size, particle size distribution, molar mass and molar mass distribution, but other properties of interest can also be determined (e.g., viscosity, or other properties related to or derivable from the diffusion coefficient, as for example, in the aforementioned equation (1) and equation (3)).
The invention is directed still further to an apparatus for characterizing a plurality of liquid samples. The apparatus comprises a sample holder suitably configured (i.e. adapted) to hold or contain an array of four or more liquid samples in combination with a probe head comprising an array of two or more fiber optic probes. The fiber optic probes are arranged to correspond to the array of samples or to a subset thereof. Each of the two or more fiber optic probes are adapted as well to simultaneously illuminate the liquid samples for analysis by light scattering, and in preferred embodiments, to simultaneously detect light scattered by the samples or components thereof. The apparatus can further comprise a translation station (e.g. such as an x-y-z robotic transfer device) for translating the sample holder and/or the probe head relative to each other. In a particularly preferred embodiment, the sample holder is adapted to present the four or more samples in a substantially coplanar relationship to each other, and the probe head comprises the two or more fiber optic probes in a substantially coplanar relationship to each other. In another particularly preferred embodiment, the apparatus can comprise the probe head in combination with two or more sample holders, preferably supported by a common sample-holder support.
The invention is also directed to analyzing various regions of a single sample in parallel. According to this approach, an array of fiber optic probes (e.g., light-scattering probes) are used to simulataneously illuminate two or more distinct regions xe2x80x94scattering volumesxe2x80x94of a single samples, and the light scattered from each of the two or more regions is detected.
Hence the methods, systems and devices of the present invention are particularly suited for screening of arrays of reaction product mixtures, such as polymerization product mixtures or formulation product mixtures, prepared in the course of combinatorial materials discoveryxe2x80x94thereby providing a means for effectively and efficiently characterizing large numbers of different materials. While such methods, systems and devices have commercial application in combinatorial materials science research programs, they can likewise be applied in industrial process applications for near-real-time process monitoring or process control.
Other features, objects and advantages of the present invention will be in part apparent to those skilled in art and in part pointed out hereinafter. All references cited in the instant specification are incorporated by reference for all purposes. Moreover, as the patent and non-patent literature relating to the subject matter disclosed and/or claimed herein is substantial, many relevant references are available to a skilled artisan that will provide further instruction with respect to such subject matter.